Histone deacetylase inhibitors (HDACi) are epigenetic modifier drugs having broad effects on gene expression by virtue of impairing histone modifications required for controlling gene transcription. HDACi can modify interferon signalling in tumor cells and thus can be utilized as viral sensitizers to enhance oncolysis. By accentuating the inherent defects in interferon responsiveness of cancer cells, these drugs are able to increase the effectiveness of tumor-tropic viruses without rendering normal cells susceptible. Thus HDACI can alter innate immunity to facilitate viral oncolysis but their impact on acquired immune responses has not been investigated in this therapeutic setting.
Viral oncolysis and cancer immunotherapy exhibit clinical efficacy as stand-alone treatments. There is an ever-growing body of literature suggesting successful oncolytic virotherapy depends on its inherent ability to induce anti-tumor immunity, leading some to go so far as to define it as a form of immunotherapy. Several promising clinical candidates are viruses that have been engineered to express immunostimulatory transgenes. However, debate continues as to whether stimulating the immune system is of net benefit to oncolytic virotherapy. Indeed, if immune responses against the oncolytic vector were inadvertently promoted, this could compromise viral replication and harm the induction of tumor-specific responses, especially when self-antigens are targeted, via mechanisms such as antigen competition, where foreign viral antigens would have a marked advantage, and reduced antigen release due to less oncolysis. Therefore, optimal strategies to combine direct oncolysis with immunotherapy should aim to promote both anti-tumor immunity and oncolytic virus replication.
Oncolytic viruses have recently been shown to be particularly potent boosters of anti-tumor immune responses. This therapeutic approach combines conventional and oncolytic viral vaccines, both expressing the same tumor antigen. Boosting with an oncolytic vaccine can lead to both tumor debulking by the virus and a large increase in the number of tumor-specific CTL (cytotoxic T-lymphocytes) in primed animals. Paradoxically, this methodology actually generates larger anti-tumor immune responses in tumor-bearing, as compared to tumor-free, animals since the replicating oncolytic vector is amplified in the tumor leading to a very large increase in the number of antigen-specific TILs and eradication of established intracranial melanomas in some cases.
Several HDACi, including valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and MS-275, are currently undergoing clinical investigations as anti-cancer drugs for various solid and hematological malignancies. Initial promising results have been obtained in acute myelogenous leukemia, T cell lymphomas and renal cell carcinoma. Interestingly, in addition to their direct anti-tumor activity, these HDACi have immunomodulatory properties. For instance, it has been shown that VPA, SAHA and MS-275 all can promote immunogenicity and immune recognition of cancer cells.